Szmuszkovicz U.S. Pat. No. 4,098,904 discloses some N-(2-aminocycloaliphatic)benzamide compounds, e.g., N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-3,4-dichlorobenzamide, and N-methyl-N-[2-(N',N'-dimethylamino)cyclohexyl]-4-bromobenzamide, and salts and hydrates thereof as analgesic (pain-reducing) drug compounds.
Szmuszkovicz U.S. Pat. No. 4,145,435 discloses some 2-aminocycloaliphatic amide compounds, e.g., N-methyl-N-[2-(N',N'-dimethylamino)cyclohexyl]-2-(4-bromophenyl)acetamide and trans-2-(3,4-dichlorophenyl)-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]acet amide, and their pharmaceutically acceptable salts as analgesic compounds.
The use object compound involved in this invention, trans(+)-2-(3,4-dichlorophenyl)-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]a cetamide, and pharmaceutically acceptable salts thereof including the maleate salt, and methods for making such compounds are described in Example 34 of Szmuszkovicz U.S. Pat. No. 4,145,435. That '435 patent refers generally to the resolution of stereo isomers. That '435 patent also discloses that preliminary pharmacological testing of the separated trans-d- and trans-1-isomers of the compound, trans-2-(3,4-dichloro-phenyl)-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]ace tamide maleate, indicated that the analgesic activity of those resolved isomers resides in the 1-isomer, but analgesic activity was also shown by the trans-dl-isomer mixtures thereof.
In Neuroscience Abstracts, 10, page 408 (October, 1984), F. C. Tortella et al report the Seizure-specific, Dose- and Time-Dependent Anti-convulsant Profile of Upjohn compound, Trans-(.+-.)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzen eacetamide by an electroshock test method. This compound is described and claimed in the above Szmuszkovicz '435 patent. However, as indicated hereinabove this compound is an analgesically active compound.
Recent pharmacology articles that may be of interest as background are:
J. Med. Chem., 1984, 27, pp. 779-782, "Anti-convulsant . . . 4-Aminobenzamides" by C. Randall Clark et al,
Science, 226, Nov. 16, 1984, pp. 850-852, "Blockade . . . Against Ischemic Damage in the Brain" by R. P. Simon et al, and
Neuropharmacology, 23, No. 3, pp. 367-371 (1984), "The Anti-convulsant . . . Electroshock Seizures in Rats" by E. F. Berman et al, although these references are not conceded to be prior art to the invention described and claimed herein.
The compound trans-(+)-2-(3,4-dichlorophenyl)-N-methyl-N-[2-(1-pyrrolidinyl]benzeneacet amide and its maleate salt (U-53,445E) is disclosed in U.S. patent application Ser. No. 06/653,385 filed Sept. 21, 1984, as being the less active enantiomer of the racemic compound, trans-2-(3,4-dichlorophenyl)-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]acet amide for treating cerebral ischemia disorders, as determined by gerbil and Fischer rat laboratory animal tests.